Submissions for variant NM_006231.4(POLE):c.3851G>A (p.Arg1284Gln)

gnomAD frequency: 0.00068  dbSNP: rs149462407

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000679625	SCV000289344	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455463	SCV000540092	uncertain significance	not specified	2016-10-31	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has not been reported in affected individuals. It is present in ExAC at a MaxMAF of 0.1%. It is classified in ClinVar as Likely Benign (1 star - Invitae). 11 mammals have a Gln at this position.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000455463	SCV000602036	benign	not specified	2019-12-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566885	SCV000671267	benign	Hereditary cancer-predisposing syndrome	2024-02-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000455463	SCV000729737	likely benign	not specified	2017-09-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
PreventionGenetics, part of Exact Sciences	RCV004529404	SCV000806767	likely benign	POLE-related disorder	2024-02-02	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455463	SCV000920079	likely benign	not specified	2018-12-14	criteria provided, single submitter	clinical testing	Variant summary: POLE c.3851G>A (p.Arg1284Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 267992 control chromosomes. The observed variant frequency is approximately 43 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3851G>A in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (3 likely benign and 3 VUS). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000679625	SCV001148891	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000455463	SCV002067012	uncertain significance	not specified	2021-06-15	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in patients with POLE-related disorders and been described in the gnomAD database with a population frequency of 0.12% in the non-Finnish European subpopulation (dbSNP rs149462407). The p.Arg1284Gln change affects a moderately conserved amino acid residue located in a domain of the POLE protein that is not known to be functional. The p.Arg1284Gln substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1284Gln change remains unknown at this time.
Sema4, Sema4	RCV000566885	SCV002536825	benign	Hereditary cancer-predisposing syndrome	2020-11-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000455463	SCV002550110	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355018	SCV001549774	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Arg1284Gln variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs149462407) as "With other allele", and in ClinVar (classified as likely benign by Invitae, GeneDx, Quest Diagnostics Nichols Institute San Juan Capistrano and as uncertain significance by Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano). The variant was identified in control databases in 167 of 267992 chromosomes at a frequency of 0.0006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 136 of 120242 chromosomes (freq: 0.001), African in 5 of 22974 chromosomes (freq: 0.0002), Other in 6 of 6324 chromosomes (freq: 0.001), Latino in 12 of 34274 chromosomes (freq: 0.0003), East Asian in 1 of 18716 chromosomes (freq: 0.0001), Finnish in 5 of 24868 chromosomes (freq: 0.0002), and South Asian in 2 of 30682 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish population. The p.Arg1284 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000679625	SCV001741157	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000679625	SCV001808871	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000679625	SCV001917867	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679625	SCV001971713	likely benign	not provided		no assertion criteria provided	clinical testing